A One‐Two Punch Strategy Against Cancer: Simultaneously Inducing and Eliminating Senescent Tumor Cells

Abstract Senolytics, an emerging class of agents that selectively deplete pro‐tumorigenic senescent cells, offer a novel adjuvant strategy to re‐engineer the tumor microenvironment and potentiate anticancer therapy. However, direct senolytic treatment poses significant safety risks, and selectively eliminating senescent cells to treat tumors remains a substantial challenge. Here, a metal‐polyphenol network (MPN) therapeutic platform operates through a “one‐two punch” strategy. The platform exploits metal‐polyphenol coordination to co‐assemble Fe 3 ⁺, folate‐terminated polyethylene glycol (PEG), a disulfide‐bridged dasatinib prodrug, and quercetin into stable nanoparticles (DQ NPs). Folate–PEG confers active tumor targeting on DQ NPs while locally released Fe 3 + pushes tumor cells into senescence, and the high intratumoral glutathione (GSH) level together with the acidic microenvironment activate the prodrug to enable dasatinib and quercetin to synergistically clear the senescent cells. Owing to their dual pH‐ and GSH‐responsiveness, these DQ NPs specifically induce senescence and then eradicate senescent tumor cells, resulting in potent tumor growth suppression. Both in vitro and in vivo studies reveal markedly superior antitumor efficacy over conventional senolytics. Comprehensive toxicological analyses further demonstrate tumor‐selective accumulation and an excellent safety profile. Collectively, our work presents a dual‐responsive MPN platform that integrates senescence induction with selective clearance, offering a new paradigm for cancer therapy.